Annals of Medicine and Surgery 74 (2022) 103315

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Annals of Medicine and Surgery

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Case Series

Acute appendicitis in pediatric patients with Coronavirus Disease 2019

(COVID-19): A case series from a developing country’s tertiary hospital
Nurnaningsih a, *, Gladys Indika Danudibroto a, Desy Rusmawatiningtyas a, Intan Fatah Kumara a,
Firdian Makrufardi a, Titis Widowati b
a
Department of Child Health, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, 55281, Indonesia
b
Department of Radiology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, 55281, Indonesia

A R T I C L E I N F O A B S T R A C T

Keywords: Introduction: and importance: A common gastrointestinal presentation of both COVID-19 and multisystem in­
COVID-19 flammatory syndrome in children (MIS-C) is acute abdominal pain, which sometimes mimics appendicitis.
Appendicitis Literature describing children with COVID-19 infection and concurrent acute appendicitis is growing, and un­
Pediatrics
derstanding these patients’ clinical picture is necessary for their proper treatment.
Case series
Case presentation: We present a case series of six healthy children before they developed classic symptoms of
appendicitis. At the same time, they were also found to have confirmed COVID-19. All patients had fever and
right lower abdominal pain. Four of six children having Alvarado score above seven had surgical treatment,
while the others only received systemic antibiotic and antiviral medication. Surgical results of two patients
revealed perforated appendicitis. No mortality occurred among them.
Clinical discussion: There is increasing recognition of gastrointestinal involvement in patients with COVID-19 and
MIS-C. There are several postulates to explain appendicitis in COVID-19. First, inflammatory response is exag­
gerated in SARS-CoV-2 infected patients. Second, obstruction of the appendiceal lumen is caused by mesenteric
adenopathy, which in turn, is caused by COVID-19 infection, not fecalith. Third, hyperinflammatory response in
MIS-C triggers inflammation in appendix.
Conclusion: Clinicians must recognize that abdominal pain with fever could be the presenting symptoms of
COVID-19 with MIS-C. MIS-C, which has severe presentations with gastrointestinal manifestations and high
mortality rate, should be considered as a differential diagnosis for a patient with appendicitis-like symptoms and
a positive SARS-CoV-2 infection.

1. Introduction manifestations of COVID-19 in pediatric patients, which are nowadays

On December 2020, the outbreak of SARS-CoV-2 infection began in
Wuhan, China and spread rapidly all over the world. Currently, several
studies postulated that COVID-19 in children appears to be milder in
clinical manifestations and the pediatric patients have a lower propor­
tion of symptomatic infection than adults [1]. Children infected with the
novel Coronavirus 2019 (COVID-19) may present with a myriad of
symptoms, including fever, cough, anosmia, nausea/vomiting, diarrhea,
and more [2].
In early May 2020, an increasing amount of evidence emerged in the
United Kingdom (UK), the United States, and Europe regarding different
known as the multisystem inflammatory syndrome in children (MIS-C)
[3]. Organ (cardiovascular, gastrointestinal, renal, hematology,
dermatology, and neurology) involvement of two or more should be
included as one of the MIS-C criteria [4]. Eighty-four percent of patients
with MIS-C have gastrointestinal symptoms (abdominal pain, nausea,
vomiting, diarrhea) as a prominent presenting characteristic [5].
Therefore, our focus was on children who tested positive for COVID-19
with primary symptoms of fever and abdominal pain, as well as the
struggle in discerning whether it is a case of appendicitis or a manifes­
tation of MIS-C. This research work has been reported in line with
PROCESS criteria [6].

* Corresponding author. Department of Child Health, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada Dr. Sardjito Hospital, Yogyakarta,
55281, Indonesia.
E-mail addresses: nurnaningsih_pri@yahoo.co.id (Nurnaningsih), indikagladys@gmail.com (G.I. Danudibroto), desy.rusmawatiningtyas@ugm.ac.id
(D. Rusmawatiningtyas), intan.kumara@gmail.com (I.F. Kumara), firdianmakruf@gmail.com (F. Makrufardi), titiswidowati@ugm.ac.id (T. Widowati).

https://doi.org/10.1016/j.amsu.2022.103315
Received 22 December 2021; Received in revised form 18 January 2022; Accepted 23 January 2022
Available online 26 January 2022
2049-0801/© 2022 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
Nurnaningsih et al. Annals of Medicine and Surgery 74 (2022) 103315

2. Case presentation
There were 392 pediatric patients admitted to a tertiary hospital with
suspected COVID-19, with 159 of them being tested positive for COVID-
19 using SARS COV-2 PCR during COVID-19 pandemic. The study was
located in one of the main university-based referral hospitals in
Indonesia. We receive pediatric patients from primary and secondary
hospitals in Yogyakarta and Central Java region. Among them, six cases
of acute appendicitis were reported among nine referral cases of COVID-
19 with appendicitis suspicion (Table 1). Patients were 3–15 years old,
with four of them being male. All patients presented primary symptoms
of both right lower abdominal pain and fever, while four patients had
vomiting, and only one patient had diarrhea. All patients were previ­
ously healthy children, with two of them being obese. Initial assessment
at admission showed two patients were in shock and were obese, which
posed comorbidities, while the others were in a stable condition. Three
patients were admitted to intensive care due to MIS-C.
Hemoglobin levels were found normal, while levels of leucocyte,
neutrophil, CRP, procalcitonin were elevated in all patients. All patients
had tested positive for SARS-CoV-2, but none of them developed respi­
ratory symptoms, and three of them had MIS-C. One of the three patients
with MIS-C had increased levels of both aspartate and alanine trans­
aminase. Positive culture was found in two patients; one result was from
peritoneal fluid (Escherichia coli), and the other was from feces (Klebsiella
pneumoniae). All patients had sterile blood cultures. Two patients, who
showed normal chest X-ray results, were either asymptomatic or had a
mild degree of COVID-19 infection. The others had COVID-19 bilateral
pneumonia with moderate to severe degree of COVID-19 infection.
Four of the six patients with Alvarado score of 7–11 had operative
treatment, and appendicitis was confirmed with a pathology examina­
tion (Fig. 1.). The two patients with Alvarado score of 4 and 6 underwent
conservative treatment with antibiotics and frequent reassessment.
From the four operative cases, surgery revealed perforated appendicitis
in two patients. In the patients of conservative treatment, abdominal

Table 1
Characteristics of research subjects.
Characteristics Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6

Age (years) 3 11 15 7 9 5
Gender Male Male Female Female Male Male
Comorbidity Obesity None None None Obesity None
Presenting 7 days of generalized 2 days of generalized 2 days of generalized 2 days of generalized 6 days of 5 days of
symptoms abdominal pain, abdominal pain, fever abdominal pain, vomiting, abdominal pain, vomiting, generalized generalized
vomiting, fever fever fever and diarrhea abdominal pain, abdominal pain,
vomiting, fever fever
Initial assessment In shock stable condition stable condition stable condition In shock stable condition
Alvarado score 9 8 10 10 6 4
Initial lab
Hemoglobin (g/ 10 (normal) 12.3 (normal) 14.4 (normal) 15.2 (normal) 11.4 (normal) 11.2 (normal)
dL)
White blood 25.92 (↑) 17.07 (↑) 15.05 (↑) 19.14 (↑) 26.67 (↑) 19.02 (↑)
count (x103/
μL)
Neutrophils 95 (↑) 79 (↑) 91.3 (↑) 87.9 (↑) 79.5 (↑) 89.4 (↑)
(x103/μL)
Lymphocytes 2.2 (↓) 10.4 (↓) 5 (↓) 6.6 (↓) 8.1 (↓) 7.2 (↓)
(x103/μL)
Platelets (x103/ 217 (normal) 316 (normal) 206 (normal) 352 (normal) 636 (normal) 355 (normal)
μL)
Blood urea 18.0 (normal) 11 (normal) 12.2 (normal) 14.2 (normal) 44.6 (↑) Not performed
nitrogen (mg/
dL)
Creatinine (mg/ 0.81 (normal) 0.55 (normal) 0.85 (normal) 0.67 (normal) 6.73 (↑) Not performed
dL)
Aspartate 7 (normal) 15 (normal) 18 (normal) 21 (normal) 29 (↑) Not performed
transaminase
(U/L)
Alanine 11 (normal) 11 (normal) 22 (normal) 14 (normal) 78 (↑) Not performed
transaminase
(U/L)
CRP >150 (↑) >150 (↑) >150 (↑) >150 (↑) 31 (↑) Not performed
Procalsitonin 10.86 (↑) 0.9 (↑) 0.7 (↑) 52.94 (↑) 31.5 (↑) Not performed
IL-6 26.71 (↑) 17.39 (↑) 84.61 (↑) 322.2 (↑) 191.5 (↑) Not performed
Respiratory No No No No No No
problems
MIS-C Yes No No Yes Yes No
Thorax x-ray Covid-19 bilateral Within normal limits Covid-19 bilateral Covid-19 bilateral Covid-19 bilateral Within normal
pneumonia pneumonia pneumonia pneumonia limits
Culture no bacterial growth no bacterial growth Not performed Escherichia coli Klebsiella Not performed
pneumoniae
Pathology acute exacerbation of appendicitis and chronic appendicitis and acute Appendicitis and Not performed Not performed
findings chronic appendicitis periappendicular periappendicular periappendicular
suppuration suppuration with suppuration with
perforation perforation
Antibiotics Yes Yes Yes Yes Yes Yes
Antiviral Yes No Yes Yes Yes No
Intensive care Yes No No Yes Yes No
Length of stay 14 7 9 8 16 5
(days)
Mortality No No No No No No

2
Nurnaningsih et al.
Fig. 1. Histopathology finding of appendicitis (a) patient 1; (b) patient 2; (c) patient 3; (d) patient 4.
pain disappeared in three and seven days after the start of antibiotic
administration. COVID-19’s specific medication was not indicated for
either asymptomatic or mild degree of COVID-19 infection, while one
was for both moderate and severe degree of COVID-19 infection. One
patient had renal impairment due to MIS-C and required four times
hemodialyses during hospitalization. Length of stay of the patients was
5–16 days. The shortest hospitalization was found in asymptomatic
COVID-19 infection, while the longest hospitalization was found in the
male patient with obesity risk, in shock, and with MIS-C. Fortunately, all
patients have recovered and been discharged.
3. Discussion
As of September 30, 2021, nearly 5.9 million children all over the
world have tested positive for COVID-19 since the onset of the pandemic
[20]. COVID-19 can manifest in different organs, such as respiratory,
gastrointestinal, neurology, and genitourinary. Thirty-two percent of the
patients had Gastrointestinal (GI) symptoms, such as diarrhea and
abdominal pain [7]. Many studies reported an increasing recognition of
gastrointestinal involvement in patients with COVID-19 and MIS-C.
Available case reports describe patients who had both typical symp­
toms of appendicitis and positive SARS-CoV-2 PCR or meet the diagnosis
for MIS-C [8]. A case found at a tertiary hospital in Jakarta, Indonesia
had similar finding with a diagnosis of acute appendicitis with gener­
alized peritonitis [21]. In our study, all of the six patients were diag­
nosed as confirmed COVID-19, with three of the cases being MISC. All
patients were hospitalized due to both fever and right lower abdominal
pain as primary concerns.
Since May 2020, there has been an increasing amount of pediatric
patients with COVID-19 infection or history of COVID-19 admitted with
hyperinflammatory shock and multi-organ involvement, recently known
as MIS-C [3]. In May 2020, in the UK, followed by in Italy and New York,
the evidence of a different manifestation of COVID-19 in the Centers for
Disease Control and Prevention (CDC) was described, which defined the
criteria for a reportable case of MIS-C as an individual under the age of
21 years. These criteria include a minimum of 24-h subjective or
objective fever ≥38 ◦ C or higher; severe illness necessitating hospitali­
zation; involvement of two or more organ systems; lab evidence of
inflammation, elevated levels in at least one of C-reactive protein (CRP),
erthyrocyte sedimentation rate (ESR), procalcitonin, fibrinogen,
D-dimer, ferritin, lactate dehydrogenase (LDH), interleukin-6 (IL-6),
neutrophils, or low albumin; and either positive SARS-CoV-2 testing by
reverse transcriptase-polymerase [9]. Patients with MIS-C have both a
severe and acute clinical spectrum with higher mortality rate [10]. In
3
Annals of Medicine and Surgery 74 (2022) 103315
patients with MIS-C, gastrointestinal symptoms were found to be 70%
[11]. This could overlap with signs and symptoms of acute appendicitis.
In a previous study, it has been reported that 11.8% of patients with
MIS-C have symptoms mimicking those of appendicitis [12]. Three of
our patients met the MIS-C criteria, with two of them being admitted
both in shock and in a state of being obese. Obesity is a high risk factor in
MIS-C since there is accumulation of inflammatory cells in adipose tis­
sue, and fat tissue-associated cytokines are proinflammatory, which
impairs respiratory function as adipose cells have more receptors
available for binding to SARS-CoV-2 [13].
Since 70% of MIS-C patients had gastrointestinal symptoms, MIS-C
shall be the first priority in differential diagnosis in patients with both
gastrointestinal symptoms and a history of recent SARS-COV-2 exposure
or infection. Malhotra et al. (2021) identified that children with COVID-
19 may present with clinical features suggestive of appendicitis. How­
ever, recent studies related to appendicitis and COVID-19 or MISC are
still lacking in numbers. There are several postulates regarding appen­
dicitis in COVID-19. First, in COVID-19 patients, the inflammatory
response is exaggerated. ACE-2 receptors, a receptor for COVID-19, are
widely distributed in both smooth muscle and endothelial cells of the
small intestines and colon, as well as arterial and venous endothelial
cells throughout the body. Second, obstruction of the appendiceal lumen
is caused by mesenteric adenopathy, which in turn is caused by COVID-
19 infection, not fecalith. Third, hyperinflammatory response in MIS-C
triggers inflammation in appendix [12]. No fecalith was detected in
four patients who had surgery, which led us to conclude that these cases
of acute appendicitis were caused by COVID-19 infection. Our results are
similar with those of Belhadjer et al. who reported a series of cases of
urgent abdominal surgery, with all patients having mesenteric lymph­
adenitis. All of them, who were initially assessed to be in shock and in
intensive care management, were patients with MIS-C. In line with our
cases, a previous study reported 71% of patients with MIS-C were
admitted to the intensive care unit [14].
Appendicitis in our patients were diagnosed based on their medical
history, as well as physical and laboratory examination. All of those
were applied to the Pediatric Alvarado score. Snyder et al. reported the
probability of appendicitis was 80%, 20%, and 6% in patients whose
scores were ≥8, 4–7, and <4 [15]. In our series, two of them, who did
not receive surgery, scored 6 and 4 in Alvarado score. Conservative
management with antibiotics was successful in managing
non-perforated appendicitis with strict inclusion criteria [19]. Earlier
study postulated the success rate of conservative treatment for
non-perforated appendicitis was 73% at 1 year [16]. A case series from
South Africa identified four children with appendicitis, confirmed by
Nurnaningsih et al.
surgical findings, in the setting of SARS-CoV-2-positive PCR. Meanwhile,
MIS-C was found in three of them after operative treatment [17,22]. A
systematic review and meta-analysis study showed that up to 41% from
1484 patients was detected SARS-CoV-2 RNA shedding in stool from
patients with gastrointestinal symptoms [23]. Another case series
identified appendicitis concomitant with acute SARS-CoV-2 infection;
all of them did not require surgery and no mortality was found [18].
The limitation of this study is that there was no confirming patho­
logical examination in patients treated with conservative management.
This study describes the presentation of cases found in one tertiary
hospital, the description of cases in other hospitals and regions may
show different results. A further multicenter study is needed to compare
our findings.
4. Conclusions
Clinician must recognize that abdominal pain with fever could be the
presenting symptoms of either COVID-19 or MIS-C. This case series
emphasizes that further investigation of COVID-19 and MIS-C should be
performed in patients with acute appendicitis. MIS-C, which can have
severe manifestations with gastrointestinal involvement and high mor­
tality rate, should be considered as a differential diagnosis for a patient
with appendicitis-like symptoms with a positive SARS-CoV-2 infection.
Reporting of these case series will help further our understanding of
COVID-19 manifestations in children. Further research should be con­
ducted to confirm these findings.
Ethical approval
The informed consent form was declared that patient data or samples
will be used for educational or research purposes. Our institutional re­
view board also do not provide an ethical approval in the form of case
report.
Funding source
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Author contribution
Nurnaningsih, Gladys Indika Danudibroto, Desy Rusmawatiningtyas,
Intan Fatah Kumara, Titis Widowati conceived the study and approved
the final draft. Nurnaningsih, Desy Rusmawatiningtyas, Firdian Mak­
rufardi, Intan Fatah Kumara and Titis Widowati drafted the manuscript,
and critically revised the manuscript for important intellectual content.
Nurnaningsih, Gladys Indika Danudibroto, Desy Rusmawatiningtyas,
Intan Fatah Kumara, Firdian Makrufardi and Titis Widowati facilitated
all project-related tasks.
Consent
Written informed consent was obtained from the patient’s parents
for publication of this case report and accompanying images. A copy of
the written consent forms is available for review by the Editor-in-Chief
of this journal on request.
Registration of research studies
researchregistry7479.
Guarantor
Nurnaningsih.
4
Annals of Medicine and Surgery 74 (2022) 103315
Provenance and peer review
Not commissioned, externally peer reviewed.
Declaration of competing interest
No potential conflict of interest relevant to this article was reported.
Acknowledgments
We want to thank all staff who were involved in the patient care.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.amsu.2022.103315.
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